Editorial: Advances and Refinements in the Development and Application of Threshold of Toxicological Concern

The Threshold of Toxicological Concern (TTC) is an exposure threshold below which there is no appreciable risk to human health. There are two main approaches: TTC values based on cancer potency data from which a one in a million excess lifetime risk is estimated and TTC values based on non-cancer effects. For the latter approach, a distribution is typically fitted to the No Observed Adverse Effect Levels (NOAELs) from repeat dose toxicity studies from which a 5th percentile value is taken and adjusted using an uncertainty factor (usually this is 100). Established TTC values are those based on oral chronic studies that were first developed by Munro et al. (1996) who subcategorised chemicals into one of three Cramer structural classes (Cramer et al., 1978). Kroes et al. (2004) presented a tiered TTC approach that established several human exposure thresholds spanning four orders of magnitude where the lowest TTC was for substances presenting structural alerts for genotoxicity (0.15 μg/d), to the next tier for organophosphates/carbamates (18 μg/d) and the remaining higher TTC values representing the same three Cramer classes originally derived by Munro et al. (1996). The World Health Organization (WHO) and the European Food Safety Authority (EFSA) (European Food Safety Authority and World Health Organization, 2016; EFSA et al., 2019) have determined that the TTC approach is a sound and fit-for-purpose risk assessment tool, with a number of caveats, in cases where chemical-specific repeat dose toxicity data are not available. More recent work has explored extending the dataset underpinning the original Cramer TTC values to demonstrate its protection and robustness (Yang et al., 2017). The work by Yang et al. (2017) was undertaken under the auspices of the EU SEURAT-1 project COSMOS whereupon a COSMOS TTC dataset was developed. This comprised 552 substances for which the toxicity data and chemical structural identifiers were carefully curated. This federated dataset was then used to derive new TTC values for two of the Cramer classes (I and III). The derived values (46 and 2.3 μg/kg bw/d respectively) have since been adopted as the current recommendations by the SCCS in relation to cosmetic substances (SCCS, 2021). In addition, a total of 476 chemicals from the RIFM (Research Institute for Fragrance Materials) dataset were added to the COSMOS/Munro TTC database for analysis, in particular bolstering Cramer class II chemicals from 40 chemicals to 111 chemicals. The derived TTC values of 49, 12.7, and 2.9 μg/kg bw/day for Cramer classes I, II or III confirm the adequacy ofMunro TTC values and further support the use of TTC for safety assessment of fragrance materials (Patel et al., 2020). Thus, these above results show that cosmetic ingredients are sufficiently represented structural classes in the current TTC dataset that had been originally developed for food. The TTC concept is scientific and convincing for it to be applied in cosmetic safety assessment. In Edited and reviewed by: Andrea Richarz, European Chemicals Agency, Finland